Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system characterized by local infiltration of T cells and macrophages into the white matter. The etiology of MS remains unknown, but both genetic and environmental factors are important in the development of disease. Susceptibility to MS has been linked to certain MHC class II alleles, although analysis of their exact function remains complicated. In this proposal, we will investigate the contribution of different human MHC class II molecules in the pathogenesis of MS. To test this, e have generated transgenic mice expressing several HLA-DR and -DQ genes in mice where the endogenous class II genes have been knocked out. In addition, to further humanize our transgenic mice, we have replaced the mouse CD4 with human CD4 gene. Our objectives are: 1) To generate experimental models of MS via induction of experimental allergic encephalomyelitis (EAE) in the transgenic lines. This analysis will shed light into the role of HLA class II molecules in susceptibility/resistance of disease. 2) To analyze the role of HLA class II molecules in cytokine expression and T cell selection. 3) To examine processing and presentation of T cell epitopes derived from CNS autoantigens, restricted by the HLA class II molecules. The development of HLA class II restricted experimental models will aid towards understanding the exact role of HLA class II molecules in MS pathogenesis and in the formulation of immunotherapeutic interventions.